This proposal is for a career development award to allow the candidate to continue his studies Of linkage strategies to locate genes associated with bipolar disorder (BP) and to better define the phenotype(s) associated with BP predisposition genes. The award will provide support for the candidate as he develops expertise in the methodology and statistical apprOaches necessary to pursue these projects. The principal mentOr will be Dr. Nelson Freimer, in whose laboratory at UCSF several linkage and positional cloning projects are now underway. Methodologies to be learned during this periOd include the use Of autOmated technOlogy for genome screening and statistical approaches to identifying genes associated with bipolar disorder in isolated populations. Dr. Lodewijk Sandkuiijl will serve as a collaborator on developing statistical methods for linkage disequilibrium analysis. The source of the data for these studies will be samples drawn from pedigree studies of BP and a separate linkage disequilibrium study of BP, both selected from the isolated Costa Rican population. High risk haplotypes for severe BP have already been identified in many of these subjects, and the candidate will learn skills for fine mapping and mutation analysis using these samples. Environmental factors which may interact with the course and severity of BP, such as drug and alcohol use, will be evaluated in both subjects from the pedigree studies and the linkage disequilibrium studies of BP. In the latter stages of this proposal, DNA from a sample of BP patients will be drawn from clinics in the San Francisco area to serve as a source for studying mutations that may be identified first in the Costa Rican population.
